Reverse vitamin k effect via photodynamic oxidation targeted at vascular endothelium, fibrin and blood platelets

ABSTRACT

A formulation or preparation for treating and preventing arterial and venous thrombi is provided. This preparation includes a non-metal containing photodynamic dye and a fat soluble vitamin. A method of administration for treatment and prophylaxis of arterial and venous thrombi is also provided. This method includes steps of: combining a non-metal containing photodynamic dye and a fat soluble vitamin; combining the non-metal containing photodynamic dye and fat soluble vitamin with a sodium solution; and administering the combination of non-metal containing photodynamic dye, fat soluble vitamin, and sodium solution as an intravenous drip.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/180,872, filed on Jul. 28, 2008, entitled “Reverse Vitamin K EffectVia Photodynamic Oxidation Targeted At Vascular Endothelium, Fibrin AndBlood Platelets.” This application is hereby incorporated by referencein its entirety.

TECHNICAL FIELD

The present disclosure relates to the formulation and administration ofa compound for the treatment and prevention of existing thrombi andassociated vascular related disease processes.

BACKGROUND AND SUMMARY

An embolus is an intravascular solid, liquid or gaseous mass thattravels through the bloodstream to a site spaced apart from its origin.The majority of all solid emboli are derived from venous and arterialthrombi. Indeed, thrombosis and embolism are so closely interrelatedthey give rise to the term thromboembolism.

Infarcts are areas of ischemic necrosis of tissue. They are usuallycaused by thromboembolic occlusion of a vessel. Thromboembolicinfarctions of the heart, lungs and brain collectively are believed toaccount for more deaths than all forms of cancer and infectious diseasecombined. Thromboembolism and infarction is further believed toconstitute the dominating clinical problems today in all industrializednations.

A variety of reactive oxygen species (ROS) have been shown to inhibit orinactivate thrombin and other serine proteases. Photodynamic dyes inbiological systems can generate the ROS which specifically targets thevascular endothelium mimicking naturally occurring redox reactions. Thisresults in targeted stimulation of the fibrinolytic system (i.e., lysisof existing thrombi). The inactivation of specific blood clottingfactors along with the resultant physiologic response to thespecifically targeted ROS, leads to an overall systemic anticoagulationstate which prevents future thrombus formation.

Present anticoagulant therapies used for inhibition of thrombi formationsuch as heparins and coumarins, have a number of untoward and sometimesunexpected effects. Discovery of the human Thrombin-activatablefibrinolysis inhibitor (TAFI) anifibrinolytic system has provided strongevidence that while the use of these anticoagulants may effectivelyprevent the formation of future thrombi, they can paradoxicallydiscourage fibrinolysis of existing thrombi. The result is a netaddition of fibrin to existing thrombi. Similarly, tissue plasminogenactivator (tPA) used to lyse existing thrombi is fraught with lifethreatening side effects. This therapy also has a narrow therapeuticwindow—less than three hours following thrombus formation. There is,thus, a need for new formulations having anticoagulant activity whichdoes not favor growth of existing thrombi and is safer and moretherapeutically flexible.

An illustrative embodiment of the present disclosure provides apreparation for treating arterial and venous thrombi. This preparationcomprises a non-metal containing photodynamic dye and a fat solublevitamin. In a further illustrative embodiment, the vitamin is vitamin K,despite being known for assisting blood clotting.

Indeed, it is known in the art that certain proteins that participate inthe blood clotting cascade are vitamin K dependent. Obviously this is adouble-edged sword. In the context of wound clotting, vitamin K can bebeneficial. In the context of pathologic blood clotting or thrombusformation within an artery or vein, however, vitamin K can beproblematic. It is therefore, believed, that vitamin K would not be anobvious choice in the field of anticoagulant pharmaceuticals

In medicine, vitamin K is used to promote the clotting of blood. Inhuman physiology, vitamin K is essential in order for the blood clottingcascade to function properly and therefore for blood to have thecapability of clotting. The subject matter of the present disclosureemploys vitamin K to create the opposite effect. When the formulation ofthe current invention is compounded in the particular order, thehydrocarbon side chain of vitamin K is cleaved from the mother quinonebase of the vitamin K derivative.

This is believed accomplished by mixing vitamin K with GeraniolTetroxane. When this combination is then mixed with verteporfin, it isbelieved that the operative porphyrin-quinone complex is generated. Itis this complex that is able to produce the necessary reactive oxygenspecies at specifically targeted sites in a ‘cyclic manner’ whichproduces said effects, not the vitamin K. If the formulation is notmixed in the proper order, it is believed that vitamin K will maintainits original structure and be available to make its usual contributionas the major promoter of blood clotting. In any event, adding vitamin Kin any way shape or form to a compound designed to prevent bloodclotting or designed to destroy existing blood clots would becounter-intuitive.

In the above and alternative embodiments, the preparation may alsoinclude: a photodynamic dye selected from a group consisting of atricarbocyanine dye, tetramethylthionine chloride dye, a xanthene dye,and a benzo-porphyrin derivative (BPD) such as verteporfin, one of thefat soluble vitamins being vitamin A, D, E and K; the fat solublevitamin being vitamin K; the photodynamic dyes being selected from agroup consisting of methylene blue, indocyanine green, rose bengal, andverteporfin; verteporfin being combined together with the fat solublevitamin; this combination being combined with a sodium salt; the sodiumsalt being sodium iodide; this combination being mixed into aphysiologic carrier solution containing a metallic additive selectedfrom the group consisting of gold, silver, copper, manganese andmagnesium; and a readily available electron donor compatible withmammalian blood.

Another illustrative embodiment of the present disclosure provides apreparation for treating and preventing arterial and venous thrombi.This preparation's formulation comprises a fat soluble vitamin combinedwith a first solvent; this combination is then diluted with a secondsolvent; a first non-metal containing photodynamic dye is thenchemically attached to the functional quinone group of the fat solublevitamin in this mixture; one to three other non-metal containingphotodynamic dyes are added to this mixture; a sodium salt is added tothis mixture; and finally a second portion of the first solvent is addedto this mixture.

In the above and alternative embodiments, the preparation may alsoinclude: the fat soluble vitamin being about 0.01 wt % vitamin K; thefirst solvent being about 20 wt % geraniol tetroxane in DMSO; the secondsolvent being about 99% DMSO; the first non-metal containingphotodynamic dye is about 0.01 wt % verteporfin; and the secondnon-metal containing photodynamic dye is about 0.0088 wt % methyleneblue; (sodium iodide solution can be substituted for IC Green) a thirdnon-metal containing photodynamic dye being about 0.0574 wt % rosebengal; the first solvent comprising dimethyl sulfoxide and carboxylicacid derivatives; the second solvent comprising dimethyl sulfoxide; thesecond non-metal containing photodynamic dye being selected from a groupconsisting of verteporfin, indocyanine green, methylene blue and rosebengal; and a sodium solution or sodium salt, such as sodium iodide in aliquid form combined with the first portion of the second solventcombined with the first non-metal containing photodynamic dye, fatsoluble vitamin, and first solvent combined with the second portion ofthe second solvent combined with the second non-metal containingphotodynamic dye.

Yet another illustrative embodiment of the present disclosure provides amethod of administration for treatment and prophylaxis of arterial andvenous thrombi. This illustrative method comprises the steps of:combining a non-metal containing photodynamic dye and a fat solublevitamin; combining the non-metal containing photodynamic dye and fatsoluble vitamin with a sodium solution, such as about 0.9% sodiumchloride (NaCl) and administering the combination of non-metalcontaining photodynamic dye, fat soluble vitamin, and sodium solution asan intravenous drip.

In the above and alternative embodiments, the method may also includeone or more of the following steps: administering the intravenous dripfor about 10 to 60 minutes; repeating the administration of theintravenous drip on a daily basis as needed for up to about eight days;combining a non-metal containing photodynamic dye that is selected froma group consisting of a tricarbocyanine dye, tetramethylthioninechloride dye, a xanthene dye and a benzo-porphyrin derivative dye;combining the fat soluble vitamin that is selected from a groupconsisting of vitamin A, vitamin D, vitamin E and vitamin K; combiningthe photodynamic dye that is selected from a group consisting ofverteporfin, methylene blue, indocyanine green and rose bengal;combining the non-metal containing photodynamic dye and fat solublevitamin with a sodium salt solution, such as sodium iodide; combiningthe non-metal containing photodynamic dye, fat soluble vitamin and saltsolution such as with a sodium chloride metallic additive; and combiningthe non-metal containing photodynamic dye, fat soluble vitamin and saltsolution with the metallic additive that is selected from a groupconsisting of gold, silver, copper, manganese and magnesium; vitamin Kbeing added to a first solvent—Geraniol Tetroxane in DMSO, this beingadded to a second solvent—99% DMSO, this being added to verteporfin,this being diluted into more of the second solvent, sodium iodide beingadded, Methylene Blue being added, rose bengal being added, this beingadded to a physiologic carrier solution such as about 0.9% SodiumChloride containing a metallic additive that is selected from the groupconsisting of gold, silver, copper, manganese and magnesium and anelectron donor that is compatible with mammalian blood such as VitaminC.

Further embodiments of the present disclosure provide compoundscontaining regioisomers of one or more of the following in combinationwith a fat-soluble vitamin, a non-metal containing benzoporphyrinderivative (BPD) photodynamic dye, and/or a synthetic tricarbocyaninephotodynamic dye, and/or a tetramethylthionine chloride dye, and/or axanthene dye for the treatment and prevention of thrombi and thrombusformation and other vascular related disease processes.

Still further embodiments of the present disclosure provide compoundscontaining regioisomers of one or more of the following in combinationwith a synthetic fat-soluble vitamin, a synthetic non-metal containingBPD photodynamic dye, a synthetic tricarbocyanine photodynamic dye, asynthetic tetramethylthionine chloride dye, or a xanthene dye fortreatment and prevention of thrombi and thrombus formation and othervascular related disease processes.

Additional features and advantages of the formulation, preparation, andadministration of the compound will become apparent to those skilled inthe art upon consideration of the following detailed descriptionsexemplifying the best mode of carrying out the formulation, preparation,and administration of the compound as presently perceived.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

An embodiment of the present disclosure is a composition that includes anon-metal containing photodynamic BPD dye such as verteporfin and a fatsoluable vitamin. In addition, or in the alternative, embodiments mayinclude, tricarbocyanine dye (indocyanine green), sodium iodide,tetramethylthionine chloride dye (methylene blue) and/or xanthene dye(rose bengal). The fat soluble vitamin for the composition may bevitamin K1.

Although this disclosure is not intended to be bound to any theory, itis believed that the photoactive substance simulates (at specificallytargeted sites) the many biological energy transductions which occurnaturally during oxidative phosphorylation in mitochondria. Aspostulated by chemiosmotic theory, a proton-motive force, orconservation of part of the energy of oxidation results from the energytransductions which produce ATP. This can be written as:

ADP+Pi+{H+}_(out)←———→ATP+H₂O+{H+}_(in)

The conserved energy appears to be interconvertible with the energy ofchemical bonds. This conserved energy maintains the flow of electronsnecessary to carry out all the biological red ox reactions to preventchemical stagnation of the biological system as a whole. Of particularinterest is the targeted simulation of naturally occurring red oxreactions. It is postulated that with the resultant cyclic creation ofproton-motive force and through energy transductions made locallyavailable for the conversion of ADP→ATP, a local deterrent to bloodplatelet aggregation and accumulation is created via rapid localdepletion of ADP. Otherwise, ADP naturally increases at the specifictarget site secondary to inflammatory condition(s) results in plateletaggregation and accumulation. It is further postulated that through thespecifically targeted local creation of a pro-oxidative milieu via thecompound of the present disclosure, there occurs a local flip in thenegatively charged vascular endothelium and the positively charged bloodplatelet electro-repulsive state (the natural anti-thrombotic state) toa locally positively charged vascular endothelium and negatively chargedblood platelet electro-repulsive state (a likewise but oppositeanti-thrombotic state).

Integrins are large binary protein complexes made up of two differenttypes of polypeptide chains (called the alpha and beta subunits) thatcome together to form a “heterodimer” that is expressed on the surfaceof a cell. A large portion of the protein is extracellular (outside ofthe cell), and just a tiny tail of a few dozen amino acids protrudesthrough the membrane on the inside of the cell. The large extracellularportions are the domains that bind to molecules on the outside of thecells and mediate the interactions of the cell with other cells.Integrins are mediators of a host of normal and abnormal biologicalprocesses. They are important for inflammation, essential for plateletaggregation after vascular injury, and involved in cell motility. Assuch, they are involved in diseases where the normal mechanisms ofplatelet aggregation go awry—as in heart attacks, strokes, and otherthrombotic events. They are also implicated in cancer metastasis. Forinstance, one of the molecules to which integrins bind is fibrinogen, acirculating dimeric protein that is present in large amounts in theblood which can bind integrins at both ends. This interaction isessential for mediating the aggregation of platelets. Platelets arecovered with integrins (typically about 80,000 are on the surface of anygiven platelet). But the integrins need to be activated to bindfibrinogen. When they are not active, the platelets flow in the bloodwithout sticking to each other or to blood vessel walls. An injury willcause the integrins to become activated. The activated integrins thenbind to fibrinogen, which then bind to other activated integrins onother platelets, cross-linking many platelets into a massive thrombus.

The final step in the activation of integrins has shown to be thebinding of talin. When talin binds to a beta subunit of β-integrin, itcauses a conformational change in the integrin which is propagatedacross the membrane, changing the structures of the integrin domainsextracellularly. Cysteine residue scanning of β-integrin, suggests“electrostatic steering” as a primary mechanism for effective plateletto endothelium and platelet to platelet adhesion. At the intracellularlevel, it is postulated that the pharmaceutical formulation of thecurrent invention prevents talin to β-integrin binding via oxidativeconformational changes in, pp 125^(FAK). (via Tyrosine protein kinaseand tyrosyl radical formation.)

Using fibronectin and the Jurkat T-cell line as a prototype model,demonstrates that fibronectin stimulates tyrosine phosphorylation ofp125^(FAK) and that crosslinking of β1-integrins by insolublefibronectin results in a 125^(FAK)/zap·70 complex and in the inductionof tyrosine phosphorylation. Disruption of this process via theformulation disclosed herein is believed to decrease WBC adhesion tofibrin and endothelial cells thereby altering (decreasing) theinflammatory process locally. These conformational perturbations havebeen elucidated through Cysteine residue scanning of β-integrin(transmembrane adhesion talin binding proteins) as sited above. Withthis disruption, the extracellular portion of the β-integrin bindingsites is altered beyond recognition (e.g., not recognized byextracellular platelet integrins) as a binding site.

It is believed that the RGD (Arg-Gly-Asp) sequence is integral in thebinding of extracellular surface integrins of platelets to vascularendothelium, collagen, prothrombin and heparin. It is, therefore,further believed that only minor changes to the extracellular portionsof transmembrane integrins will lead to lack of their recognition by theRGD sequence. The platelet to platelet, platelet to endothelium and/orplatelet to fibrin binding capacity are believed to be inhibited by theformulations of the present disclosure favoring anticoagulation and ornormalization of blood flow.

In mitochondria, it is believed that H atoms removed from substrates aredonated to the respiratory chain (porphyrins) and transferred tomolecular oxygen forming the ROS superoxide. Through the action ofsuperoxide dismutase (SOD) and then catalase, superoxide degenerates tohydrogen peroxide and then molecular oxygen and water with resultantenergy production. Proton-motive force allows for this chain of eventsto occur even in the absence of an oxidizable substrate. It is furtherbelieved that the formulation of the present disclosure likewise locallyallows for these specifically targeted transductions of energy andresultant transformations in relevant enzyme systems even in the absenceof an oxidizable substrate thereby contributing to local fibrinolysisand the overall antithrombotic state thereby locally achieved.

Porphyrin generated ROS via the dark effects of verteporfin arespecifically targeted to an existing thrombus via parenteraladministration of the present formulation. The majority of these ROSsare believed to be superoxide. The chemical structure of an embodimentof the formulation incorporates the functional quinone group of vitaminK as a side chain of verteporfin. It is believed this porphyrin-quinonecomplex produces desired effects at specifically targeted sites in acyclic manner.

Vitamin K is labile to oxidation and responsible for the activationand/or synthesis of plasma clotting factors VII, IX and X in the liver.The compositions of the present disclosure depletes vitamin K andthereby depletes vitamin K dependent plasma clotting factors in theliver and thereby at specifically targeted sites. The functional quinonegroup of vitamin K is incorporated as a side chain of verteporfin. Whenthe constituents are mixed in the correct order, the functional quinonegroup portion of vitamin K is borrowed to chemically bond toverteporfin. The hydrocarbon chain (tail) of vitamin K is cleaved off.Accordingly, vitamin K is being used as a building block for the moreimportant molecule, the porphyrin-quinone complex. This molecule iscapable of performing re dox reactions in a cyclic manner. The “reversevitamin K effect” refers to the final outcome of the lysis andprevention of clots. It is not meant to imply that vitamin K is itselfdoing the opposite of what it normally does. The results are believedaccomplished by the combined effects of the ROS generated atspecifically targeted sites. The formulations of this disclosure mayabolish and or normalize the sequleae of existing thrombi, possibly forup to about eight months following their formation, while simultaneouslypreventing the formation of future thrombi.

An illustrative manufacturing process for one of the formulations is asfollows: adding about 20 mg. of vitamin K (10 mg/ml) to about two ml. ofa solvent containing about 80% dimethylsulfoxide (DMSO) and about 20%carboxylic acid derivatives; diluting resulting composition in about 100mls 99% DMSO; dissolving 15 mg. of verteporfin (lipholized cake) intothe composition; separately adding about 25 mg. of indocyanine green(lypholized cake) and/or about 10 mg methylene blue (10 mg/ml.) intothat solution; then combining 65 mg of rose bengal powder into thatsolution; and finally adding 14 more mls. of 80% DMSO and about 20%Geraniol Tetroxane (carboxylic acid derivatives) to that solution;resulting in about 119 mls. of the subject formulation.

Another illustrative formulation is as follows:

DMSO=100 mls.=110,000 mg.=97.0617% (80%-99%)

Geraniol Tetroxane=16 mls.=3200 mg.=2.8236% (0.0002%-20%)

Vitamin K=2 mls.=20 mg.=0.0176% (0.0001%-1%)

Verteporfin=15 mg.=0.0132% (0.0001-1%)

Methylene Blue=1 ml.=10 mg.=0.0088% (0.00001-1%)

Sodium Iodide=0.4 ml.=20 mg.=0.0176% (0.0001-1%)

Rose Bengal=65 mg=0.0574% (0.0005-1%)

It can be appreciated that if IC Green is used, sodium iodide can beomitted and visa versa. Other dyes that could be used are other naturalor synthetic porphyrins, chlorophyllins, hemins, porphins, corrins,texaphrins, hematoxylin, eosin, erythrosine, flavinoids, lactoflavin,anthracene dyes, hypericin, methylcholanthrene, neutral red andflourescein. It is also appreciated that the quantities and percentagescan vary.

A method of administration for treatment and prophylaxis of arterial andvenous thrombi using the previously illustrated preparation comprises:combining about one cc of sodium ascorbate (500 mg/ml) to 100 cc. of 0.9NaCl; adding about one half (0.5) cc of the subject formulation;administering as an IV drip to the patient for ten to sixty minutes;repeating on a daily basis as needed for up to eight days. Prophylaxisof future thrombus formation is achieved by administration of about twocc of the subject formulation about every three to four months. It isalso believed that other related vascular disease states can be treatedby administration of the subject formulation.

It is believed that formulations of the present disclosure targets oneor more of the following conditions: vascular endothelium and areas ofvascular endothelial injury, thereby negatively effecting theaggregation of blood platelets in areas of vascular endothelial injury;fibrin of existing arterial and venous thrombi, thereby negativelyeffecting the aggregation of blood platelets and the net addition offibrin to, and within, arterial and venous thrombi; fibrin in muralthrombi within the heart chambers, thereby preventing atrialfibrillation induced micro-thrombi within the atrial heart chambers;fibrin within thrombi formed in the low blood flow area of an arterialaneurysm, thereby preventing arterial thromboembolism; bone marrowresulting in normalization of bone marrow derived blood forming elementsthereby increasing immune function; macrophage foam cells withinatheromatous plaque; atheromatous plaque within coronary arteries;atheromatous plaque within carotid arteries; atheromatous plaque withincerebral arteries; atheromatous plaque within renal arteries;atheromatous plaque within peripheral arteries; neovascular endotheliumand drusen within retinal arteries; collagen and vascular smooth muscleconstituents within occluded and partially occluded man made arterialstenting devices, man made venous stenting devices, human vein to arterybypass graft anastomoses and human artery to artery bypass graftanastomoses thereby increasing blood flow within these devices andanastomoses; vascular endothelium within varicose veins; vascularendothelium within superficial veins.

It is further believed that the formulations of the present disclosurepromote one or more of the following: debulking of atheromatous arterialplaque and retinal arteriolar drusen and extravasation of cholesterolwithin arterial walls, resulting in increased blood flow and therebyimproving cardiac function, brain function, kidney function and skeletalmuscle function while reducing symptoms of angina in coronary arterydisease, transient ischemic attack in carotid artery occlusive disease,senile dementia in cerebral artery occlusive disease, hypertension inrenal artery occlusive disease, claudication in peripheral arteryocclusive disease and decreased visual acuity in the dry form of agerelated macular degeneration; stabilization of atheromatous arterialplaque resulting in decreased risk of myocardial infarction, transientischemic attack and cerebrovascular accident; treatment and preventionof Thrombotic Thrombocytopenic Purpura (TTP); treatment and preventionof Dissiminated Intervascular Coagulopathy (DIC); treatment andprevention of phlebitis; treatment and prevention of congestive heartfailure (CHF); treatment and prevention of pulmonary embolism (PE);treatment and prevention of cardiac arrhythmias; treatment of peripheralneuropathies and peripheral venous stasis ulceration associated withdiabetes mellitus; treatment of rheumatoid arthritis and a variety ofother auto-immune diseases and disorders; treatment of Type IV delayedhypersensitivity reactions such as delayed drug reactions; treatment ofanemias; treatment of chronic pain; treatment of chronic fatigue andfibromyalgia; and treatment of infectious diseases.

It is even further believed that the formulations of the presentdisclosure can have an effect on one or more of the following:minimizing varicose veins; obliterating of spider nevi, vascular purpuraand the lesions which represent the epidermal changes of chronic lowerextremity edema and upper extremity micro-vascular fragility;normalizing blood lipid constituents; balancing endogenous hormoneproduction thereby normalizing endocrine function; and increasingspermatozoa count thereby increasing male fertility.

The disclosure is further illustrated but is not intended to be limitedby the following examples.

Example 1

A 65 year old female suffered a fall which inflicted trauma to the leftlower extremity above the knee. There was diffuse edema present and thepatient was experiencing extreme pain. Ambulation was difficult. Avenous angiodynagram duplex scan of the left lower extremity revealednoncompressability with acute thrombus formation in the common femoral,superficial femoral and popliteal veins. The patient was hospitalizedand anticoagulated with heparin over the following two weeks. She wassent home on coumadin and anti-inflammatory medication. The left lowerextremity continued to be diffusely swollen. The patient required 10 mg.of hydrocodone four times per day to deal with the pain in the leftlower extremity. The patient was non-ambulatory for all practicalpurposes. Over the next three to four weeks there was no improvement inthe patient's condition. The patient was given an intravenous infusionof 0.5 cc of the subject formulation in 100 cc 0.9% NaCl and 1 cc ofsodium ascorbate (500 mg/ml). She described immediate relief of pain.Ambulation was improved to near normal within the first 24 hoursfollowing the intravenous infusion. The patient no longer required painmedication. All symptoms of swelling disappeared in the week followingthe intravenous infusion. Infusion was repeated two months later as aprecautionary and preventative measure.

Example 2

Three days following endoscopic “cleaning up” of the left knee jointwith repair of the medial collateral ligament, a 53 year old maledeveloped painful swelling and erythema in the left calf while keepinghis left lower extremity elevated following the surgery. VenousAngiodynagram revealed a large thrombus in the left politeal vein. Thepatient refused hospitalization. One week later the patient was given anintravenous infusion of 1 cc of the subject formulation in 100 cc 0.9%NaCl and 1 cc of sodium ascorbate (500 mg/ml). There was some immediaterelief of pain following the intravenous infusion. The following day aninfusion of 2 cc of the subject formulation was administered in the samemanner. All symptoms of pain and swelling in the calf disappeared on theday of the second intravenous infusion. A repeat Angiodynagram thefollowing week revealed dissolution of the thrombus.

Example 3

A 74 year old male suffered from swelling behind his right knee. He hada known Baker's cyst but also noticed some recent enlargement behind theright knee and the area was more painful than usual. There was alsoincrease in temperature to touch in the area. Arterial Angiodynagram ofthe right lower extremity revealed an aneurysm of the popliteal artery,8-10 cm in length and 4-5 cm in width. There were multiple thrombiwithin the low pressure, low flow area of the aneurysm. There alsoappeared to be a pseudoaneurysm superimposed over an area of the trueaneurysm. The patient was given a total of 3 ccs of the subjectformulation over three weeks by intravenous infusion. Pain was reducedin the area behind the patient's knee and the knee joint became moremobile with less apparent inflammation following the initial treatment.Repeat arterial Angiodynagram three weeks later revealed completeresolution of the arterial thrombi within the aneurysm. The arterialAngiodynagram was repeated approximately one year later and although theaneurysm had grown approximately 2-3 cm in length, there were still nosignificant thrombi present within the aneurysm. The patient currentlyreceives a total of 2 ccs of the formulation of the current inventionevery three to four months for prevention of thrombus formation.

Example 4

A 57 year old male with severe varicose veins in both lower extremitiespresented with a popliteal deep venous thrombosis in the right lowerextremity three days post arthroscopic knee surgery. He had a history ofdeep venous thrombosis and had previously had multiple varicosities tiedoff in the right lower extremity to prevent thromboembolism. He wasanticoagulated. Eight months later he was still taking 6 mgs. ofCoumadin daily and still had pain and swelling in the area of the DVT.He was also experiencing pain in both lower extremities due to musclecramps and described generalized weakness in both lower extremities. Thepatient was given a total of 1 cc. of the subject formulation over threedays. Following the second 0.25 cc. administration on day two oftreatment, the pain and swelling in the area of the DVT completelyresolved.

The “knot” where the DVT had been was no longer palpable. Over severaldays following the third administration, the patient was no longerexperiencing cramping in his lower extremities and he stated that bothof his legs were feeling stronger. A repeat Angiodynagram was orderedthree weeks later which showed dissolution and resolution of thepatient's thrombus.

Although the present disclosure has been described with reference toparticular means, materials and embodiments, from the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of the present disclosure and various changes andmodifications may be made to adapt the various uses and characteristicswithout departing from the spirit and scope of the present invention asset forth in the following claims.

1. A preparation for treating arterial and venous thrombi comprising: aphotodynamic dye; and a fat soluble vitamin.
 2. The preparation of claim1, wherein the photodynamic dye is selected from a group consisting of abenzoporphyrin derivative (BPD) dye, tricarbocyanine dye,tetramethylthionine chloride dye and a xanthene dye.
 3. The preparationof claim 1, wherein the fat soluble vitamin is selected from a groupconsisting of vitamin A and vitamin E.
 4. The preparation of claim 1,wherein the photodynamic dye is selected from a group consisting of averteporfin, methylene blue, indocyanine green and rose bengal.
 5. Thepreparation of claim 1, wherein the non-metal containing photodynamicdye and the fat soluble vitamin are combined with a sodium solution. 6.The preparation of claim 1, wherein the non-metal containingphotodynamic dye and the fat soluble vitamin are combined with a sodiumchloride solution.
 7. The preparation of claim 1, further comprising ametallic additive.
 8. The preparation of claim 7, wherein the metallicadditive is selected from a group consisting of gold, silver, copper,manganese and magnesium.
 9. The preparation of claim 1, furthercomprising a physiologic carrier solution containing a readily availableelectron donor compatible with mammalian blood.
 10. A preparation fortreating arterial and venous thrombi comprising the followingformulation: a fat soluble vitamin combined with a first solvent; afirst non-metal containing photodynamic dye combined with the fatsoluble vitamin combined with the first solvent; a second solvent;wherein a first portion of the second solvent is combined with the firstnon-metal containing photodynamic dye, fat soluble vitamin, and firstsolvent; a second non-metal containing photodynamic dye; wherein asecond portion of the second solvent is combined with the secondnon-metal containing photodynamic dye, and wherein the first portion ofthe second solvent combined with the first non-metal containingphotodynamic dye, fat soluble vitamin, and first solvent is combinedwith the second portion of the second solvent combined with the secondnon-metal containing photodynamic dye.
 11. The preparation of claim 10,wherein the formulation further comprises: the first solvent is about 20wt % geraniol tetroxane in DMSO; the second solvent is about 99% DMSO;the first non-metal containing photodynamic dye is about 0.0132 wt %verteporfin; and the second non-metal containing photodynamic dye is <5wt % sodium iodide of IC Green if IC Green is used or 0.0176 wt % sodiumiodide if sodium iodide replaces IC Green.
 12. The preparation of claim11, further comprising a third non-metal containing photodynamic dyebeing about 0.0574 wt % rose bengal.
 13. The preparation of claim 10,wherein the first non-metal containing photodynamic dye is verteporfin.14. The preparation of claim 10, wherein the first solvent comprisesdimethyl sulfoxide and carboxylic acid derivatives.
 15. The preparationof claim 10, wherein the second solvent comprises DMSO.
 16. Thepreparation of claim 10, wherein the second non-metal containingphotodynamic dye is selected from a group consisting of verteporfin,indocyanine green, and methylene blue.
 17. The preparation of claim 10,further comprising a sodium solution that is combined with the firstportion of the second solvent combined with the first non-metalcontaining photodynamic dye, fat soluble vitamin, and first solventcombined with the second portion of the second solvent combined with thesecond non-metal containing photodynamic dye.
 18. The preparation ofclaim 11, further comprising about 0.0132% benzoporphyrin derivative.19. The preparation of claim 11, further comprising a third solvent ofabout 2.8236 wt % geraniol tetroxane in DMSO.
 20. A method ofadministration for treatment and prophylaxis of arterial and venousthrombi comprising: a) combining a non-metal containing photodynamic dyeand a fat soluble vitamin; b) combining the non-metal containingphotodynamic dye and fat soluble vitamin with a sodium solution; and c)administering the combination of non-metal containing photodynamic dye,fat soluble vitamin, and sodium solution as an intravenous drip.
 21. Themethod of claim 20, further comprising the step of administering theintravenous drip for about 10 to 60 minutes.
 22. The method of claim 21,further comprising the step of repeating the administration of theintravenous drip on a daily basis for up to eight days.
 23. The methodof claim 20, further comprising the step of combining a non-metalcontaining photodynamic dye that is selected from a group consisting ofa tricarbocyanine dye, tetramethylthionine chloride dye and a xanthenedye.
 24. The method of claim 20, further comprising the step ofcombining the fat soluble vitamin that is selected from a groupconsisting of vitamin A and vitamin E.
 25. The method of claim 20,further comprising the step of combining the photodynamic dye that isselected from a group consisting of a verteporfin, methylene blue andindocyanine green/sodium iodide and rose bengal.
 26. The method of claim20, further comprising the step of combining the non-metal containingphotodynamic dye and fat soluble vitamin with the sodium solution thatis a sodium chloride solution.
 27. The method of claim 20, furthercomprising the step of combining the non-metal containing photodynamicdye, fat soluble vitamin, sodium solution with a metallic additive. 28.The method of claim 20, further comprising the step of combining thenon-metal containing photodynamic dye, fat soluble vitamin, sodiumsolution with the metallic additive that is selected from a groupconsisting of gold, silver, copper, manganese and magnesium.
 29. Apreparation of treating arterial and venous thrombi comprising: about0.0088 weight percent methylene blue, about 0.0176 weight percent sodiumiodide, about 0.0574 weight percent rose bengal, and the balance beingan intravenous solution and a fat soluble vitamin.
 30. The preparationof treating arterial and venous thrombi of claim 29, wherein theintravenous solution further comprises about 2.8236 weight percentgeraniol tetroxane in DMSO, about 97.0617 weight percent DMSO, and about0.0132 weight percent benzoporphyrin derivative.